Steroid Hormones and Tumour Development

Hormone

A chemical substance produced in the body that controls and regulates the activities of certain cells or organs

signal transmission over long distances, stability in the blood

A key property of hormones is ________, thus requiring _______.

non-steroidal and steroidal

The two broad groups of hormones are…

peptides, membrane receptors, secondary messengers

Non-steroidal hormones are _____ that bind _____ (therefore they act as _______).

androgens or glucocorticoids, intracellular receptors

Steroidal hormones are ______ that bind ______.

Prostate cancer, Skene’s gland carcinoma

____ is the most common cancer in males, while ______ is very rare and accounts for less than 0.003% of all genital tract cancers in females.

Wolffian ducts regression, Müllerian ducts develop into fallopian tubes, uterus, and upper vagina due to lack of AMH inhibition, and external genitalia develop

In the female (XX) embryo, the absence of high levels of testosterone causes:

AMH causes Müllerian ducts to disappear, stabilisation of the Wolffian ducts which develop into the epididymis, vas deferens, and seminal vesicles, and DHT causes the penis and scrotum to form

In the male (XY) embryo, high levels of testosterone causes:

Anti-Müllerian Hormone (AMH)

Produced by the Sertoli cells, causes the Müllerian ducts to wither and disappear in the male embryo

Dihydrotestosterone

A potent byproduct of testosterone which is responsible for forming the penis and scrotum in the male embryo

Nuclear Receptors

Transcription factors that regulate the expression of specific genes during development, cell differentiation, reproduction, and homeostasis

ligand-dependent, steroids, non-steroids, products of lipid metabolism

Many NRs regulate target gene expression in a ______ manner, and typical ligands include ______, ______, and ______.

androgenic hormones, testosterone and DHT

Androgen receptors are bound by _______ such as…

estrogen, ligand-independent, alpha and beta homo- or heterodimers

Estrogen receptors are bound by ______, also have ______ functions, and are composed of…

E2-ERs directly bind the ER elements in target gene promoters

The classical mechanism of ER signalling is:

nuclear E2-ER complexes bind a transcription factor complex that contacts the target gene promoter

ERE-independent genomic actions of ER signalling:

growth factors trigger protein kinase cascades leading to phosphorylation which activates nuclear ERs at EREs

Ligand-independent genomic actions of ER signalling:

membrane E2-ER complexes trigger protein kinase cascades that lead to altered functions of proteins in the cytoplasm

Non-genomic ER signalling:

gluconeogenesis, insulin sensitivity, insulin resistance and fatty liver

Estrogen causes ______ and _____ in the liver leading to _______ in excessively high levels.

lipolysis, lipogenesis, glucose uptake, insulin sensitivity, obesity, adipose inflammation, altered secretory profiles

Estrogen causes _____, _____, _____, and _____ in adipocytes leading to ______, _____, and ______ in excessively high levels.

insulin sensitivity, glucose uptake, insulin resistance, impaired glucose homeostasis

Estrogen causes ______ and _____ in skeletal muscle leading to ______ and ______ in excessively high levels.

insulin secretion, increased beta cell function, type 2 diabetes, beta cell dysfunction

Estrogen causes _____ and _____ in the pancreas leading to _____ and ___

food intake, energy expenditure, obesity

Estrogen causes ______ and _____ via the hypothalamus leading to _____.

cell proliferation and growth, PI3K and MAPK activation, cell cycle progression, cyclin D1 via c-myc, angiogenesis, VEGF, apoptosis inhibition, Bcl2

Estrogen and testosterone drive _______ via ________. Upregulation of ER/AR targets leads to _____ (via ___), _____ (via ____), and _____ (via ____).

synthesis rates, form while in circulation, metabolism in target tissue, and receptor expression

The bioavailability of circulating steroid hormones is determined by:

hydrophobic/lipophilic, carrier protein, SHBG, albumin, unbound, bioavailable fraction

Steroid hormones are _____, therefore they need a ______ while in the blood. 60-80% bind ______, 20-40% bind ______, and 2% is _____ (and serves as the _______).

Sex hormone-binding globin (SHBG)

Binds steroid hormones in the blood and can mediate signalling from the cell surface as a complex via the SHBG receptor

cholesterol

All steroid hormones are derived from…

estradiol, estrone, estriol, and estetriol

There are 4 major endogenous forms of estrogen:

estradiol, estetriol

The most potent form of estrogen is ______, and _____ is only produced during pregnancy.

testosterone, dihydrotestosterone, and androstenedione

The 3 major androgens (in males) are:

DHT

The most potent (male) androgen is…

20, 22 desmolase

_______ converts cholesterol to the first precursor for steroid hormones.

5alpha-reductase, finasteride and dutasteride

______ converts DHT to testosterone and vice versa and can be inhibited by ______.

p450 aromatase

_____ converts testosterone to estradiol

LHRH, pituitary, LH and FSH, ovaries and prostate

The hypothalamus produces ______ which acts on the _______ which releases ______ which acts on the _______.

estrogen, testosterone, LHRH release by the hypothalamus

Upon LH and FSH stimulation, the ovaries produce ______ and the prostate produces _______. These both inhibit…

Oophorectomy

Removal of the ovaries

Orchiectomy

Removal of the testes

intracellular DNA binding proteins

Steroid hormone receptors are…

steroid hormone passes through the cell membrane and binds its receptor in the cytoplasm or nucleus > hormone/receptor complex enters the nucleus and binds DNA causing gene transcription > protein synthesis is induced

Steps of steroid hormone signalling:

X chromosome, single protein with variants, dimer

The androgen receptor gene is located on the _______ and is a _______. It functions as a ______.

two separate genes, alpha ER, beta ER, splice variants, homo- or heterodimer

The estrogen receptor is _______ (_____, which is upregulated in cancer, and _____, which is downregulated in cancer). Each have _____ and function as ________.

simultaneous binding of two promoter HRE sites, dimerisation, coregulatory proteins, gene specificity, promoter chromatin remodelling, recruitment and stabilisation of transcription machinery

Action of steroid hormones at DNA requires ______, therefore ______ is essential. They bind _______ which regulates ________, and they serve two functions: _______ and _______.

cell surface receptors, activating membrane channels, modulating calcium signalling, activating ROS and eNOS pathways, and influencing apoptosis

Aside from DNA, estrogen can bind ______, thus ________, _______, _______, and ______.

Sarcoma

Cancer of the connective/soft tissues, e.g. bones or muscles or fat, which are rare

Carcinoma

Cancer of the epithelial tissues, e.g. skin or organ linings, which are very common

ducts or lobuli, carcinomas, sarcomas

Breast cancer typically originates from cells in the _______, and majority of cases are ______ (<1% are ______).

ductal carcinomas, lobular carcinomas

Of invasive breast cancers, ~80% are _______ and ~10% are _______.

Estrogen, gender affirming hormone therapy

_____ levels are a risk factor for breast cancer, with a Dutch cohort study showing that transwomen who received _______ having higher risk of breast cancer compared to cisgender men.

Klinefelter Syndrome

Syndrome wherein a man carries two or more copies of the X chromosome; associated with increased risk for male breast cancer

increased risk of invasive breast cancer, breast cancer-specific mortality, reduce this risk

Exposure of high levels of estrogen during a woman’s lifetime is associated with _______ and ______ in post-menopausal women. However, exogenous estrogen used as hormone replacement therapy may ________.

only in a subset of luminal epithelial cells, naturally ER-, luminal, lose ER expression

In healthy breast tissue ER is expressed _______ and basal cells are _______. ER+ breast cancers almost always originate from the _____ lineage, though ER- tumours can originate from the same lineage when they ______.

luminal progenitor cells, even though the parent cell was a luminal progenitor the cancer genetic reprogramming can turn off the ER gene and turn on basal-like genes

Most triple-negative breast cancers in patients with BRCA1 mutations arise from ________. This is because…

luminal origin, does not automatically mean the cancer started in basal cells

ER positivity is a reliable marker for ______, but ER negativity…

well differentiated, better short-term

ER+ cancers are usually _______, leading to _______ prognosis when compared to ER- cancers.

respond well to initial treatment, can remain dormant and recur 10-20 years later, recur quickly or not at all

Luminal origin cell have a “slower” biological clock, so while they _______ they can ______ unlike basal-origin cancers which tend to _______.

bones

ER+ luminal origin breast cancer has a preference to metastasize to the ______, and is one of the most classic examples of the “seed and soil” hypothesis.

hormone metabolism byproducts, e.g. catechols

Estrogens can cause direct DNA damage from…

decreases cancer progression, inhibiting ER signalling, decreasing tumour cell migration

While the role of progesterone in cancer is not well understood, evidence indicates that it ________ by ______ and ______.

hormone action and hormone production

If a cancer is hormone dependent, it can be slowed or stopped by interfering with:

estrogen and testosterone, less toxic

The main targets of hormone therapy are _________, and endocrine agents are ______ compared to traditional cytotoxic chemotherapies.

Antagonist

Substance that stops the action or affect of another substance, e.g. by binding and blocking the receptor

Agonist

Substance that causes the same action as the target substance, e.g. by binding and activating the same receptor

selective estrogen receptor modulator (SERM), estrogen antagonist

Tamoxifen acts as a _________ that functions as a _______ in breast tissue.

inhibit aromatases involved in estrogen production, post-menopausal women, high estrogen levels from the ovaries

Aromatase inhibitors, which ________, are used to treat breast cancer in _______ as is does not work with _______.

selective estrogen receptor degrader (SERD), binding and destabilising the estrogen receptor, proteasomal degradation

Fulvestrant acts as a _________ and functions by _______, causing ______.

ER conformational change, DNA binding but no transcription, degradation of ER after binding

SERMs have 2 mechanisms of action: they induce _________ (therefore there is _________), or they induce _________.

pro-drug, activation to become more potent metabolites, Polymorphisms or inactivation of conversion enzymes

Tamoxifen is a _______, therefore it requires ________. _________ change a patient’s responsiveness.

blocking conversion of androgens to estrogen

Aromatase inhibitors work by…

LHRH analogues, downregulate LHRH receptors and inhibit LH secretion, medically induced menopause

_______ can create constant, artificially high levels of LH and FSH, thus eventually ________ and therefore there is less estrogen production by the ovaries. This is referred to as “_______” and is often used in conjunction with other therapies.

AR+, erythroblast transformation-specific TF (ETS) functioning, AR activity, PTEN functioning

Prostate cancers are uniformly ___ and are instead classified based on ______ (which regulates _____) and _____.

ineffective, alternate AR activation pathways

In prostate cancer treatment anti-androgen therapy is ______ as there are _______.

very slow, remain asymptomatic, less well correlated with molecular phenotype

Prostate cancer has ______ progression and most patients _______. Outcome is _______ compared to breast cancer.

hypothalamic-pituitary-gonadal, adrenal axis

The _______ and ______ in prostate cancer serves as a therapeutic target.

adenohypophysis, adrenocorticotropic hormone (ACTH), androgens, DHEA-S

LHRH release by the hypothalamus stimulates _______ of the pituitary to produce ________ which stimulates the adrenal gland to produce ______ (predominantly ________) which is released into the circulation. These are converted to DHT by the prostate.

androgen withdrawal, initially respond, chemical orchiectomy via LHRH agonists, competitively binding anti-androgens, anti-enzymes for 5alpha-reductase

A key strategy for treating prostate cancer involves ______ to decrease proliferation or increase apoptosis. 80% of men ______. First line involves _______, while second line therapies involve ______ and _____.

increase in LH and testosterone production, suppression of LH, suppression of testosterone

Initial overstimulation by LHRH receptors by LHRH agonists leads to ________, and chronic administration leads to _______ and thus _______. The same effect can be acieved through LHRH antagonists.

downregulation of LHRH receptors, immediate blocking LHRH receptors

Chronic use of LHRH agonists leads to ______ while use of LHRH antagonists leads to _______.

inhibit androgen de novo steroidogenesis

At the adrenal level, abiraterone is used to…

competitively inhibits DHT binding thus inhibiting nuclear translocation and DNA binding, highly selectively competitively binds AR and accelerates AR degradation

At the prostate level, AR inhibitors are used and have different mechanisms of action. Enzalutamide _________, while bicalutamide ________.

De novo adrenal androgen steroidogenesis, cholesterol, DHEA-S, steryl-sulfatase, bile salt sulfotransferase

________ occurs in the adrenal glands, wherein ______ is converted to ______ with the aid of enzymes _______ and _______.

binding the AR and causing receptor degradation

SARDs work by _______, subsequently causing tumour regression.

inhibiting enzymes involved in adrenal steroidogenesis, 5alpha-reductase inhibitors, block testosterone conversion into DHT

AR inhibitor abiraterone works by _______. Dutaseride and finasteride are _______ that functions to _______.

Cyclical administration, Limited doses of androgens, some cell differentiated, preserves AR expression and androgen sensitivity, apoptosis in remaining cells

_________ minimises side effects of androgen inhibitors and increases time to onset of castration resistance. _________ keeps ________ (which _________) and a new round of androgen inhibition continues to drive ________.

increased hormone resistance, intrinsic, loss of ER/AR at tumour onset, acquired, epigenetic

"Progession” in prostate and breast cancers appears as ________, which has 2 forms: ______ (which is _______) or _______ (which is largely ________).

ER expression, different ER status, rare, ER gene expression is determined by epigenetics

Hormone resistance can occur as ER primary cancers can be heterogeneous for _______ and metastases can have _______ from the primary tumour. Mutations/amplifications are _____ as _______.

Decrease in tamoxifen metabolising enzymes, decreased production of the active form of tamoxifen

_______ can create tamoxifen resistance in ER cancers, causing ______.

Ligand independence, EGF and PI3K and IGF1

______ can create hormone resistance in ER cancers, especially through crosstalk with growth receptors for _________.

receptor amplification, is retained even if androgen insensitivity develops

In prostate cancer, genetic events like ______ are common and AR expression _________, creating hormone resistance.

Ligand independence, EGF and IGF1, ETS gene fusion, PTEN mutations, increased PI3K signalling

______ in prostate cancer can create hormone resistance through crosstalk with growth factor receptors for ________, ______ events, or _______ that cause _______.